Many drugs are required to be taken up by cells or pass through cells and/or be taken up by cellular organelles to reach their intended therapeutic target. Many larger molecules and some small ones by themselves have limited capacity to pass through cellular membranes. The capacity to pass through cellular membranes can be increased by linking a pharmacological agent to an internalization peptide (also known as protein transduction domains, or membrane translocation domains). These peptides include tat, antennapedia peptide and arginine-rich peptides. These peptides are short basic peptides present in many cellular and viral proteins and serve to mediate translocation across membranes. A common feature of these peptides is their highly cationic nature. Such peptides have been reported to facilitate uptake of many different peptide and proteins into cells, as well as oligonucleotides, peptide nucleic acids and small molecules and nanoparticles. Uptake into cells and organelles and across the blood brain barrier has been reported.
As one application of internalization peptides, a tat peptide has been linked to a peptide inhibitor of interaction between postsynaptic density-95 protein (PSD-95) and NMDARs (Aarts et al., Science 298, 846-850 (2002)). The resulting chimeric peptide was tested in cellular and an animal model of stroke. The chimeric peptide was taken up into neuronal cells and found to reduce ischemic brain damage in the animal model. This result has led to the proposal to use peptide antagonists of PSD-95/NMDAR linked to an internalization peptide for treating stroke and other diseases mediated by excitotoxicity.